An anatomical pathologists' insight into health

With an intense insight into pathology, Professor Marjorie Walker’s work explores several facets: pathology in the gut in dyspepsia and irritable bowel syndrome, the relationship between brain and gut health in gastroenterology, coeliac disease and also unique biomarkers in prostate cancer.

As an anatomical pathologist, Marjorie is the person who traditionally looks down the microscope and diagnoses biopsies to assess normal, inflammatory or cancerous specimens. This vital role is a buffer between the patient and clinician, dealing directly with doctors rather than patients. Marjorie explains that the role is more of a doctor’s doctor – making a diagnosis that the doctor then explains to the patient.

Studying medicine in the UK at the University of Nottingham, Marjorie took a turn on a fortuitous path to anatomic pathology from general practice. Facing a two month gap between the completion of study and commencing General Practice, and not wanting to be idle, Marjorie approached the pathology department to see if there were any jobs available. Marjorie’s honours year study in pathology led to an appointment as a temporary lecturer; teaching and researching in pathology. “Halfway through the term I thought to myself, ‘I actually really like this’ and realised that I didn’t particularly want to go into General Practice. I wanted to stay looking down the microscope and looking after patients that way. I also really enjoyed the teaching side of academia, which is why I’ve stayed halftime academic and halftime diagnostic pathologist,” Marjorie adds.

Here at the University of Newcastle, Marjorie is co director of the Priority Research Centre for Digestive Health and Neurogastrogenterology with Laureate Professor Nick Talley.

At some point in their lives, roughly twenty to twenty five per cent of Australians will have a functional GI disorder: either irritable bowel disorder or functional dyspepsia or both. Within the Priority Research Centre for Digestive Health and Neurogastroenterology Marjorie and an innovative team of researchers are working hard to look at the pathology behind those conditions.

With a focus on exploring the association with the brain, the team is examining how we can alleviate the symptoms by treating the brain or by treating the gut. However, it’s not just treatment looking to treat and alleviate the symptoms, the aim is to actually resolve the underlying physiology behind the conditions.

Marjorie and the team are looking at gut/brain, brain/gut problems: “We know that there are people who have a functional GI disease who have psychological problems such as anxiety and depression. We also know that sometimes in people who have anxiety and depression they can then develop a GI disorder. So our question is what comes first? Brain/gut or gut/brain?”

A fifty / fifty chance

In looking at the studies, and following people up over an extended period of time, what the team has found is that what comes first is in the region of 50/50. “With fifty per cent of those who have a functional disorder it is preceded by an anxiety disorder and in fifty per cent of those who have an anxiety disorder, it is preceded by a gut disorder,” Marjorie adds.

“With treatment options we know that Cognitive Behavioural Therapy is very effective in some people, particularly those with irritable bowel syndrome. However in those patients, not everybody responds, so what we need to do now is to look to see if those who don’t respond – which way around are they – gut to anxiety or anxiety to gut? That’s work that we’re doing across the country, collaborating with researchers across the east coast,” Marjorie explains.

Marjorie’s primary area of interest is in gastroenterology, looking at functional diseases. “These diseases are called ‘functional’ because they don’t have so-called ‘pathology’ and it’s difficult to understand why people have pain if they don’t have pathology. So we’ve decided to look very carefully at some of the outer reaches of pathology, particularly innate-immunity (such as allergy) and what we found in a large series of studies is that patients with functional GI disease (functional dyspepsia and IBS) have got an innate immune problem which we’re now trying to address with treatment. We have found an asthma like reaction in the duodenum (which connects the stomach to the intestine) in dyspepsia.

The treatment involved is a type of anti-asthma treatment. “We’re doing a trial at the moment where we’re ‘damping down the eosinophils’ (a type of white blood cell) in the duodenum using a slow-release steroid which is really poorly absorbed, so people don’t get steroid side-effects. However, they do get the local effects of the steroid shutting down the eosinophils which is what we think is causing the damage and the pain.” In IBS we have found a bug (colonic spirochaetosis) in a small proportion of those with IBS, which is exciting as these respond to antibiotic treatment.

The work in this PRC will have an enormous impact on the health of our nation. These GI conditions may not be terminal conditions, but they do impact seriously upon people’s life. “Giving people a happier life makes for a happier and more productive nation,” Marjorie concludes.

Looking into biomarkers for prostate cancer

The other side of Marjorie’s research involves looking at biomarkers for prostate cancer, another aspect of anatomical pathology. “The molecular people find clever things such as expression of a protein, and they find that in a lab when they look at levels of protein in a test tube. But what we really need to know is what’s going on in the tissues, so I act as the bridge between the lab and the clinician. So if we look at a piece of tissue, we try to discover how much of this protein is being expressed and in what cells and which disease.”

“I’ve been working with Professor Hubert Hondermarck on a very exciting neurotrophic factor called proNGF which is over-expressed in really bad prostate cancers. We’re now looking at circulating proNGF and we’re looking at expression in a whole range of cancers to see if we can use it as a biomarker to tell whether this is a particularly bad cancer,” Marjorie explains.

One of the problems with prostate cancer is that it’s extremely common – in fact a high proportion of men over 70 will be impacted by prostate cancer. However, some of these cancers are very slow growing, and may not be life-threatening. So how do we know if a cancer’s one to worry about? “As one of my colleagues at Imperial College, London used to say ‘We need to find the tigers amongst the pussycats’.” Marjorie says.

“What I try to do with prostate cancers is to suss out the tigers, and we think we’ve found a way to do that and we’re currently working on refining the method at the University of Newcastle. We’re making great strides and we’re being recognised as the only people to be working in this field in Australia,” Marjorie concludes.

An international focus

Marjorie is adamant that research is not about being isolated, but is about working in collaboration with people around the country and also internationally.

“With my gastroenterology research we have a nationwide collaboration with the Australian Gastrointestinal Research Alliance (AGIRA), and with Laureate Professor Nick Talley and we collaborate with an array of teams in Sweden, in the US and in Europe - it’s a global connection.”

Marjorie also has an interest in coeliac disease and has produced guidelines in conjunction with other coeliac researchers so that health practitioners have a concerted way of looking at patients and dealing with them. “Guidelines are produced by evidence, and evidence-based medicine is the best way to practice medicine,” Marjorie explains.

For example, helping people living with coeliac make the difficult transition from being an adolescent with coeliac to an adult with coeliac is one area that Marjorie has recently helped to produce guidelines for.

“We’ve also recently completed a large study looking at the prevalence of coeliac disease in the Hunter Valley, and we’re now just trying to unravel what the condition is. One in three Australians do not consume gluten now, which makes diagnosis even more difficult as the duodenum will look normal if a person’s not consuming gluten and deciding if coeliac disease is a true diagnosis really requires a gluten challenge,” Marjorie says.

Career Summary

Biography

Research ExpertiseMy expertise as a histopathologist is in interpretation of clinical or molecular events in tissue sections, correlating both routine pathology and immunocytochemistry to demonstrate particular cells or their function or secretion with clinical patient data. My routine pathology skills lie in Dermatopathology, Urology and Gastrointestinal Pathology. I principally research in gastrointestinal and urological pathology. In Urology I particularly focus on prostate cancer research. My current research in gastrointestinal pathology is focused on finding biomarkers and pathology pathways in functional bowel diseases, named functional as there is no discernible organic pathology. Over the next 5 years I plan to complete the investigation of functional bowel disorders and other gastrointestinal disorders to unravel the pathology which occurs in these diseases, and hope to elucidate the cause of these distressing conditions with the aim of devising effective agents for treatment. I also work on coeliac disease, particularly defining parameters for diagnosis of coeliac disease in conjunction with the International Coeliac Definitions Group.

Teaching ExpertiseMy teaching experience extends across Undergraduate, Masters and Postgraduate levels. I have taught histopathology to undergraduate and graduate entry students from basic principles to systems pathology. I contribute to course design, exam development and marking – In our curriculum review at the JMP I wish to ensure that students see the integration of pathology into clinical medicine. I have lectured on principles of pathology to wide ranging groups, and I give invited lectures at National and International meetings.

Administrative ExpertiseI have extensive administrative experience at University level in teaching and admissions to medicine previously at Imperial College.

Chair of the Admissions committee for the JMP.

I undertake review of papers for Gut, American Journal of Gastroenterology, Alimentary Pharmacology and Therapeutics, Histopathology, Clinical Gastroenterology and Hepatology, Journal of Clinical Pathology, European Journal of Gastroenterology and Hepatology, Clin Chem Acta, European Journal of Surgical Oncology and the British Journal of Medical and Surgical Urology. I also review grants for CRUK and NHMRC (Australia) and am an Editorial Board member of Alimentary Pharmacology and Therapeutics.

I am a member of the Hunter Cancer Biobank, Flagship (Biomarkers) and Management committees, setting up of new histology facilities, supervising Biobank tissue validation and facilitation of cancer research projects at HMRI.

Collaborations

Our research centre, the Australian GastroIntestinal Research Alliance (AGIRA) is an umbrella for our research in the gut

Chile/ Leeds UK - I am an expert advisor to the Content study - funded by the EU, a study on iron deficiency and infection in the gastrointestinal tract in children in Brazil, Chile and London- Professor Jean Crabtree, Leeds, UK, Dr Paul Harris, Santiago, Chile.

Member of the International Coeliac Definitions Group – an international group of physicians with a prime interest in coeliac disease, defining management and diagnosis of coeliac disease.

Qualifications

Bachelor of Medical Science (Honours), University of Nottingham - UK

Bachelor of Medicine, Bachelor of Surgery, University of Nottingham - UK

Communication between the brain and gut is not one-way, but a bidirectional highway whereby reciprocal signals between the two organ systems are exchanged to coordinate function. ... [more]

Communication between the brain and gut is not one-way, but a bidirectional highway whereby reciprocal signals between the two organ systems are exchanged to coordinate function. The messengers of this complex dialogue include neural, metabolic, endocrine and immune mediators responsive to diverse environmental cues, including nutrients and components of the intestinal microbiota (microbiota-gut-brain axis). We are now starting to understand how perturbation of these systems affects transition between health and disease. The pathological repercussions of disordered gut-brain dialogue are probably especially pertinent in functional gastrointestinal diseases, including IBS and functional dyspepsia. New insights into these pathways might lead to novel treatment strategies in these common gastrointestinal diseases. In this Review, we consider the role of the immune system as the gatekeeper and master regulator of brain-gut and gut-brain communications. Although adaptive immunity (T cells in particular) participates in this process, there is an emerging role for cells of the innate immune compartment (including innate lymphoid cells and cells of the mononuclear phagocyte system). We will also consider how these key immune cells interact with the specific components of the enteric and central nervous systems, and rapidly respond to environmental variables, including the microbiota, to alter gut homeostasis.

The precursor for nerve growth factor (proNGF) is expressed in some cancers but its clinicopathological significance is unclear. The present study aimed to define the clinicopatho... [more]

The precursor for nerve growth factor (proNGF) is expressed in some cancers but its clinicopathological significance is unclear. The present study aimed to define the clinicopathological significance of proNGF in thyroid cancer. ProNGF expression was analysed by immunohistochemistry in two cohorts of cancer versus benign tumors (adenoma) and normal thyroid tissues. In the first cohort (40 thyroid cancers, 40 thyroid adenomas and 80 normal thyroid tissues), proNGF was found overexpressed in cancers compared to adenomas and normal samples (p < 0.0001). The area under the receiver-operating characteristic (ROC) curve was 0.84 (95% CI 0.75-0.93, p < 0.0001) for cancers versus adenomas, and 0.99 (95% CI 0.98-1.00, p < 0.0001) for cancers versus normal tissues. ProNGF overexpression was confirmed in a second cohort (127 cancers of various histological types and 55 normal thyroid tissues) and using a different antibody (p < 0.0001). ProNGF staining intensity was highest in papillary carcinomas compared to other histological types (p < 0.0001) and there was no significant association with age, gender, tumor size, stage and lymph node status. In conclusion, proNGF is increased in thyroid cancer and should be considered as a new potential diagnostic biomarker.

The neuronal membrane protein sortilin has been reported in a few cancer cell lines, but its expression and impact in human tumors is unclear. In this study, sortilin was analyzed... [more]

The neuronal membrane protein sortilin has been reported in a few cancer cell lines, but its expression and impact in human tumors is unclear. In this study, sortilin was analyzed by immunohistochemistry in a series of 318 clinically annotated breast cancers and 53 normal breast tissues. Sortilin was detected in epithelial cells, with increased levels in cancers, as compared to normal tissues (p = 0.0088). It was found in 79% of invasive ductal carcinomas and 54% of invasive lobular carcinomas (p < 0.0001). There was an association between sortilin expression and lymph node involvement (p = 0.0093), suggesting a relationship with metastatic potential. In cell culture, sortilin levels were higher in cancer cell lines compared to non-tumorigenic breast epithelial cells and siRNA knockdown of sortilin inhibited cancer cell adhesion, while proliferation and apoptosis were not affected. Breast cancer cell migration and invasion were also inhibited by sortilin knockdown, with a decrease in focal adhesion kinase and SRC phosphorylation. In conclusion, sortilin participates in breast tumor aggressiveness and may constitute a new therapeutic target against tumor cell invasion.

Irritable bowel syndrome (IBS) is a functional disorder defined by symptoms in the absence of overt pathology. Colonic spirochetosis (CS), defined by histologic observation of spirochetal strains of Brachyspira in colonic biopsies, is uncommon and considered of doubtful significance. We aimed to determine the prevalence of CS in the general population, identify subtle colon pathologies, and evaluate a link with symptoms of IBS. Colonoscopy was performed in 745 subjects (aged 19-70 years, mean age 51 years, 43% male) with biopsies (ileum and 4 colonic sites) from a random population sample, Stockholm, Sweden, who completed a validated questionnaire of gastrointestinal symptoms; IBS was identified by Rome III criteria. CS was identified by histology and immunohistochemistry. In a general population, 17 individuals (2.28%; 95% confidence interval, 1.2%-3.5%) were diagnosed as having CS by histology; 6 (35%) had IBS. CS was always present in the sigmoid colon, but only 14 rectal biopsies. Eosinophils were increased in colon biopsies in CS cases versus controls, in the transverse (P =.02), sigmoid colon (P =.001), and rectum (P =.0005) with subepithelial eosinophil clusters (P =.053). Lymphoid follicles (at any site) were present in 13 CS (P =.0003). There was a 3-fold increased risk of IBS in CS (odds ratio, 3.59; 95% confidence interval, 1.27-10.11; P =.015). Polyps and diverticular disease were similar in CS cases and controls. The prevalence of CS in a general population is 2% and associated with nonconstipating IBS. Colonic eosinophilia with lymphoid follicles may signify the presence of CS.

A multidisciplinary panel of 18 physicians and 3 nonphysicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD.

Aims/hypothesis. Uncoupling proteins are mitochondrial transmembrane carriers implicated in the regulation of energy balance. Dysfunction of UCP3 (the predominant uncoupling protein in skeletal muscle) might therefore be expected to reduce thermogenic capacity, alter energy homeostasis and influence predisposition to obesity and Type II (non-insulin-dependent) diabetes mellitus. A variant in the putative promoter region of UCP3 (-55 cÂ¿t) has recently been identified, and an association with obesity reported in French subjects. Our aim was to study the pathophysiological role of this variant in diabetes-related and obesity-related traits using two distinct ethnic populations. Methods. The -55 cÂ¿t variant was genotyped in 85 South Indian and 150 European parent-offspring trios ascertained through Type II diabetic probands and in 455 South Indian subjects initially recruited to an urban survey into the prevalence of diabetes. Results. In South Indian and European parent-offspring trios there was no preferential transmission of either allele at the -55 cÂ¿t polymorphism to diabetic offspring (South Indians, p = 0.60; Europeans, p = 0.15). When family members were analysed for intermediate traits, the t-allele was associated with increased waist-to-hip ratio but only in females (South Indian mothers p = 0.036, daughters p = 0.032: European mothers p = 0.037, daughters p = 0.14). These findings were replicated in South Indian females from the population-based survey (p = 0.039). Conclusion/interpretation. The consistent association between the t-allele at this locus and increased waist-to-hip ratio in women from three separate data sets indicates that variation at this polymorphism (or another locus with which it is in linkage disequilibrium) influences fat distribution but that this effect is restricted to females.

Background The importance of the host in influencing the outcome of H. pylori (Hp) infection is becoming increasingly accepted. The identity of the host genes involved, however, r... [more]

Background The importance of the host in influencing the outcome of H. pylori (Hp) infection is becoming increasingly accepted. The identity of the host genes involved, however, remains unknown. Potential candidate genes include MHC class II genes, cylokine genes and genes involved in mucosal protection and repair. Aim The purpose of this study was to determine if certain polymorphisms, of known functional significance, in the tumour necrosis factor (TNF), Interleukin (IL)-l, IL-10 and mannose binding lectin (MBL) genes, were associated with outcome of Hp infection. Methods From a large DNA bank, matched case and control cohorts of 100150 subjects each of duodenal ulcer (DU), Hp+ non-ulcer dyspepsia (NUD) and Hp-NUD were assembled. Gene polymorphisms were screened by PCR followed by restriction fragment length polymorphism analysis (for TNF308 and IL-1 Ã-511 ) or by sequence specific oligonucleotide hybridisation techniques. Allele frequencies were compared between the groups using standard odds ratios and chi squared tests. Results Four TNF and two IL-10 polymorphisms were studied and showed no association with outcome. However individuals homozygous for allele 2 of the IL-1 receptor antagonist gene intron 2 VNTR did show a trend towards increased risk of ulcer (p=0,09). This is the same allele that has been associated with increased severity of inflammation in ulcerative colitis and SLE. The MBL codon 52 mutation was found in 15% of Hp+ patients but only 4% of uninfected controls; odds ratio -3.97 (95%CI 1.33-15.94), p=0.007. Conclusions A known deficiency in innate immunity has been shown to predispose to Hp infection. No genes associated with particular outcome of infection have yet been identified.

The association of gastric adenocarcinoma of intestinal type with gastric lymphoma is well established and the sequence of events leading to this outcome has been studied extensiv... [more]

The association of gastric adenocarcinoma of intestinal type with gastric lymphoma is well established and the sequence of events leading to this outcome has been studied extensively in the past year. Significant developments include recognition of differing host response to Helicobacter pylori, co-factors and the strain of the bacteria in the malignant process. The successful treatment of low grade B cell lymphomas with antimicrobial therapy is further evidence that this tumour is a result of H. pylori infection, although caution must be exercised in selecting suitable cases for treatment.

Objectives: To determine the quality of duodenal ulcer healing following treatment with standard regimens of Helicobacter pylori eradication, or with omeprazole, ranitidine and de... [more]

Objectives: To determine the quality of duodenal ulcer healing following treatment with standard regimens of Helicobacter pylori eradication, or with omeprazole, ranitidine and de nol. Design: The study was designed to determine whether changes in gastric metaplasia and microvilli occur at an ultrastructural level before and after various treatments. Patients and methods: Twelve patients with duodenal ulcers (nine males, three females), all judged positive for H. pylori by the [ 13 C]-urea breath test, were studied. Biopsies were obtained immediately before treatment and 1 month later. Four standard treatment regimens were instituted for 1 month, comprising (1) 1 week of eradication therapy (one tablet de nol each day, 500 mg amoxycillin each day and 2 g metronidazole on each of the last 3 days), (2) 40 mg omeprazole each morning, (3) 300 mg ranitidine each morning and (4) one tablet de nol each day. The groups were matched for age and sex. Gastric (fundus, body and antrum) and duodenal biopsies (edge of duodenal ulcer or its scar) were taken and studied by light microscopy; the duodenal biopsies were also examined by electron microscopy. All ulcers were endoscopically healed after 1 month. Results: After treatment, all the biopsies in the eradication group were negative for H. pylori, but present in one or more sites in all the other treatment groups. However, the duodenal inflammatory response decreased in all groups. There was no apparent change in gastric metaplasia or the quality of microvilli in response to any of the four treatments. Conclusions: Healing of ulcer sites after eradication of H. pylori is a prolonged process. At the ultrastructural level, epithelial integrity was not restored within the time-scale of this study.

Research Collaborations

The map is a representation of a researchers co-authorship with collaborators across the globe. The map displays the number of publications against a country, where there is at least one co-author based in that country. Data is sourced from the University of Newcastle research publication management system (NURO) and may not fully represent the authors complete body of work.